A long-term goal of our laboratory is to understand the role of apolipoprotein (apo-) E in cholesterol metabolism. Apolipoprotein E is associated with various lipoproteins in the plasma. It mediates their binding to the apo-B,E(LDL) receptor, resulting in the uptake of these lipoproteins and the regulation of intracellular cholesterol metabolism. Our recent studies have suggested that apo-E also plays an important role in lipid transport and metabolism within the central and peripheral nervous systems. In addition, following injury to peripheral nerves, a dramatic increase in apo-E production is observed. The correlation of this increase with regeneration suggests a role for apo-E in the regulation of axon regrowth and remyelinization. The first aim of this proposal is to study the role of apo-E in lipid transport and cholesterol homeostasis in the nervous system. In the central nervous system we will characterize the apo-E- and apo-A-I- containing lipoproteins in cerebrospinal fluid to determine the source of their lipids. Additionally, we will determine the distribution of apo-B,E(ldl) receptors in both the central and peripheral nervous systems, as well as whether these receptors are regulated by plasma cholesterol levels. The second aim is to explore the possible role of apo-E-mediated lipid transfer during nerve regeneration. Tissue culture experiments will be used to test the importance of apo-E-containing lipoproteins and apo- B,E(LDL) receptors for axon elongation and myelinization. Additionally, a study of regenerating and nonregenerating nerve models by immunocytochemistry, electron microscopy, and biochemistry will be used to ascertain the relationship of specific cellular events to apo-E secretion, apo-B,E(LDL) receptor expression, and lipoprotein accumulation in the nerve. The in vivo levels of apo-E levels of apo-E will also be manipulated in various model systems in at attempt to modulate axon elongation or remyelinization. The third aim is to determine whether apo-E may have an effect on neural tissue that is unrelated to lipid transport and homeostasis. The effect of apo-E on the adhesion of neurons to extracellular matrix proteins or on their extension of axons in response to growth factors will be determined. Together, these studies will help elucidate the role of apo-E in normal nervous tissue and in nerve regeneration.